Palladium-catalyzed intramolecular cyclization of o-ethynylbenzoic acids and o-ethynylbenzamides: Preparation of isocoumarins and isoquinolin-1-ones

Article abstract of DOI:10.1055/s-1999-3522

Treatment of the o-ethynylbenzoic acids 1A with a catalytic amount of Pd(II) and triethylamine resulted in the 6-endo-dig cyclization to give the 3-substituted isocoumarins 3 as major products in moderate to good yields. Similarly, the palladium-catalyzed

Full text of DOI:10.1055/s-1999-3522

PAPER
1145
Palladium-Catalyzed Intramolecular Cyclization of o-Ethynylbenzoic Acids
and o-Ethynylbenzamides: Preparation of Isocoumarins and
Isoquinolin-1-ones
Haruki Sashida,* Atsushi Kawamukai
Faculty of Pharmaceutical Sciences, Hokuriku University, Kanagawa-machi, Kanazawa 920–1181, Japan
Fax +81(76)2292781; E-mail: h-sashida@hokuriku-u.ac.jp
Received 24 February 1999; revised 17 March 1999
synthesis of isocoumarins was described. It has also been
Abstract: Treatment of the o-ethynylbenzoic acids 1A with a cata-
reported that silver salts10 were effective for the 5-exo-dig
lytic amount of Pd(II) and triethylamine resulted in the 6-endo-dig
cyclization of the o-alkynylbenzoic acids 1A affording the
cyclization to give the 3-substituted isocoumarins 3 as major prod-
phthalides as major products. Castro and co-workers11 de-
ucts in moderate to good yields. Similarly, the palladium-catalyzed
cyclization of o-ethynylbenzamides 1B also proceeded but afforded scribed that the reaction of o-halobenzoic acid 2 with cu-
only the isoquinolin-1-ones 3B.
prous acetylides resulted in a direct ring closure to give
the 3-methylidenephthalides 4A. Moreover, the palladi-
um–copper-catalyzed heteroannulation of o-iodobenzoic
acid 2 with alk-1-ynes affording the 3-alkylidenephtha-
lides (major products) and the isocoumarins (minor prod-
ucts) was reported by Kundu and co-workers.12 Among
them, cyclization of the o-alkynylbenzoic acids 1A cata-
lyzed by palladium has not yet been reported.
Key words: o-ethynylbenzoic acid, o-ethynylbenzamide, 6-endo-
dig cyclization, isocoumarin, isoquinolin-1-one
Heterocyclic ring formation by the intramolecular annula-
tions of carboxylic acids,1 alcohols,2,3 amines4,5 and
amides6 to a carbon–carbon triple bond is a well-docu-
mented procedure. Mercuric salts,7 ruthenium3 and palla-
dium(II)1,2,4,6 have been used as effective catalysts for the
above ring-closure reactions. Various synthetic methods
for the preparation of the isocoumarin skeleton have been
investigated. In particular, the 3-substituted derivatives8
are attractive synthetic targets because of their biological
and pharmacological activities. Recently, the palladium-
catalyzed cyclization of o-alkenylbenzoic acids9 for the
On the other hand, we have previously reported the syn-
thesis of the five-membered heterocycles 6, 8 containing
a chalcogen element (Te, Se or S) as shown in Scheme
1.13, 14 The tellurophenes, selenophenes and thiophenes 613
are easily obtained from the o-bromoethynylbenzenes 5
via the intermediates 7 in one pot. Compounds 9, 14 which
are the chalcogeno analogs of the parent benzoic acids 1A,
were regio- and stereospecifically cyclized to give the tel-
R
R
CuC
HC
C R
Ag
C
C R
I
O
+
O
or
COOH
C
R
COOH
O
O
3A
Pd[II]
4A
2
1A
R
C
X
C R
1) SOCl2
2) NaHM
1) t-BuLi
R
M
M
2) M
O
3) EtOH
5: X = Br
1A: X = COOH
8: M = Te, Se
6: M = Te, Se, S
C
C
R
C
C R
C
O
MH
MH
7
9
Scheme 1
Synthesis 1999, No. 7, 1145–1148 ISSN 0039-7881 © Thieme Stuttgart · New York

1146
H. Sashida, A. Kawamukai
PAPER
luro- or seleno-phthalides 8 without any catalysts. Fur- the triple bond have more difficulty during the 6-endo-dig
thermore, we have recently demonstrated the synthesis of ring closure due to their steric hindrance. Thus, the 5-exo-
the tellurium- or selenium-containing heterocycles using dig reaction also proceeded. All the isocoumarins 3A and
an intramolecular ring closure involving a carbon–carbon the phthalides 4A were well characterized by satisfactory
triple bond.15 In connection with our studies, we became spectroscopic (MS, IR and 1H NMR) and analytical data,
interested in the palladium-catalyzed cyclization of the and the isocoumarins 3Aa–d were identical with the au-
o-ethynylbenzoic acids 1A. In this paper, we describe thentic samples.16 The stereochemistry of the alkene moi-
simple methods for the palladium-catalyzed regioselec- ety of 4A and 10 was determined by the nuclear
tive ring closure of the o-ethynylbenzoic acids 1A and the Overhauser enhancement (NOE) measurement. In the
o-ethynylbenzamides 1B, which led to the isocoumarins case of the former, the NOE was observed between the 3’-
3A and the isoquinolinones 3B as major products, respec- H and the aromatic 4-H in the 400 MHz 1H NMR spectra
tively.
of 4Ac. Thus, the alkene moiety was determined to have
(Z)-stereochemistry. The latter has the NOE between the
alkenic 3’-H and the methylene protons of the butyl group
at the C-2 position. Thus, the stereochemistry of the alk-
ene moiety of 10 was determined to be the (E)-form.
The key starting materials, the o-ethynylbenzoic acids 1A,
were already prepared in our previous work,14 and the
o-ethynylbenzamides 1B were also easily obtained from
the o-bromoethynylbenzenes 513a as shown in Scheme 2.
Compounds 5 were lithiated with tert-BuLi in anhydrous Next, we examined the ring closure reaction of N-butyl-o-
THF at –80 °C and then treated with butyl isocyanate ethynylbenzamides 1B. PdPhCH2Cl(Ph3P)2 was found to
(BuNCO) to afford the benzamides 1B in one pot in good be a more effective catalyst than PdCl2(MeCN)2 in this re-
yields (66–90%) except for the TMS derivatives 5e, action. The reaction of 1B with this palladium catalyst and
which gave the amide 1Be in 27% yield together with the Et3N in refluxing THF afforded the 3-substituted isoquin-
direct cyclized product 10 (59% yield) under these condi- olin-1-ones 3Ba, b, d, which were the sole isolated char-
tions.
acterized products. In this case, the 5-exo-dig cyclization
products 4B were not obtained in spite of the careful ex-
periment. The ring closure of the amides 1Bc and 1Be,
which have a bulky group, also did not occur because of
their definite steric hindrance at the adjacent position. The
starting materials were decomposed without giving any
products under these conditions. These results are summa-
rized in Scheme 3.
C
C R
1) t-BuLi
C
C R
2) n-BuNCO
Br
C
O
NH n-Bu
5
1B
a: R = Me
b: R = n-Bu
c: R = t-Bu
d: R = Ph
3'
R
TMS
3'
H
4
R
C
C
R
e: R = TMS
4
Pd [II]
3
5
6
3
5
6
+
X
2
X
N
n-Bu
C
O
XH
2
1
7
1
O
O
7
O
10
1A: X = O
B: X = Nn-Bu
4
3
Scheme 2
Aa R = Me
81%
73%
b
Bu
c
t-Bu
48%
56%
38%
23%
41%
Cyclization of the o-ethynylbenzoic acids 1A was first ex-
amined. Thermal (e.g., refluxing in xylene), acid (e.g.,
TsOH) or silver salt (e.g., AgNO3) promoted and anionic
(e.g., BuLi) cyclization could not proceed, while
PdCl2(Ph3P)2, PdPhCH2Cl(Ph3P)2, PdCl2 and Pd(OAc)2
were less effective for this reaction. PdCl2(MeCN)2 and
PdCl2(PhCN)2 usually gave good results for the cycliza-
tion of 1A. Acetonitrile is the most suitable solvent, and
the addition of a base (e.g. triethylamine) was essential for
the reaction. In certain cases (1Aa–d), the isocoumarins
3A, which were produced by the 6-endo-dig cyclization of
1A, were found to be the predominant products. It is noted
that the phthalides 4A, the 5-exo-dig reaction products,
were also obtained when the substituent was t-Bu, Ph or
TMS. This ring-closure result clearly indicates that these
Ph
d
e
TMS
31%
Ba
b
R = Me
75%
77%
Bu
Ph
d
64%
Scheme 3
Mps were measured on a Yanagimoto micro melting point hot stage
apparatus and are uncorrected. IR spectra were determined with a
Hitachi 270–30 spectrometer. Mass spectra (MS) and HRMS were
recorded on a JEOL JMS-DX300 instrument. NMR spectra were
benzoic acids 1Ac–e having a bulky group at the end of determined with a PMX-60SI (60 MHz), JEOL EX-90A (90 MHz)
or JEOL JNM-GSX 400 (400 MHz) spectrometer in CDCl3 using
Synthesis 1999, No. 7, 1145–1148 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Palladium-Catalyzed Intramolecular Cyclization
1147
TMS as internal standard. Microanalyses were performed in the Mi-
croanalytical Laboratory of this Faculty.
1H NMR (60 MHz): d = 0.25 (9H, s, TMS), 0.93, 1.2–1.7 and 3.44
(3H, t, J = 6.0 Hz, 4H, m and 2H, br t, J = 7 Hz, N-Bu), 7.2–7.5 and
7.8–8.0 (3H, m and 1H, m, PhH), 7.7 (1H, br, NH).
HRMS m/z: M+ Calcd for C16H23ONSi: 273.1549. Found:
N-Butyl-o-ethynylbenzamide 1B; Typical Procedure
To a stirring solution of o-bromoethynylbenzene 5 (10 mmol) in an-
hyd THF (50 mL) at –80 °C under Ar was slowly added t-BuLi (1.6
mol/l in pentane solution, 9.38 ml, 15 mmol). The mixture was
stirred under these conditions for 1 h. A solution of BuNCO (1.49
g, 15 mmol) in THF (5 mL) was added to the mixture, and then the
cooling bath was removed. The mixture allowed to warm to r.t., and
stirred for an additional 12h. The mixture was quenched by pouring
into ice-water, and extracted with CH2Cl2 (3 x 100 mL). The com-
bined organic layer was washed with brine (2 x 100 mL), dried
(MgSO4), and evaporated in vacuo. The resulting residue was chro-
matographed on silica gel using CH2Cl2–acetone (30:1) as eluent to
give pure 1B. The crystalline product was recrystallized from
EtOAc–hexane. In the case of TMS derivative 5e, the isoindolone
10 was also obtained in these conditions.
273.1551.
(E)-N-Butyl-3-(2’-trimethylsilyl)methylideneisoindolone 10
Yellow oil; 1.60 g (59%).
MS: m/z = 273 (M+).
IR: n = 1712 cm–1 (C=O).
1H NMR (400 MHz): d = 0.29 (9H, s, TMS), 0.83–0.92, 1.29–1.36,
1.53–1.62 and 3.69–3.73 (3H, m, 2H, m, 2H, m and 2H, m, N-Bu),
5.23 (1H, s, 3’-H), 7.42–7.78 (4H, m, PhH).
HRMS m/z: M+ Calcd for C16H23ONSi: 273.1549. Found:
273.1549.
Cyclization o-Ethynylbenzoic Acid 1A: Fomation of Isocou-
marin 3A and (Z)-3-Methylidenephthalide 4A; Typical Proce-
dure
1Ba (R = Me): colorless prisms, mp 79–80 °C; yield: 1.53 g (71%).
MS: m/z = 215 (M+).
To a mixture of 1A (1mmol) and Et3N (0.5 ml) in anhyd THF (20
mL) was added PdCl2(MeCN)2 (25 mg, 0.1 mmol). The mixture
was stirred at r.t. until disappearance of the starting material (about
6–12 h). Water was added to the mixture, and the resulting aqueous
mixture was extracted with Et2O (3 x 50 mL). The combined organ-
ic extract was washed with brine (2 x 100 mL) dried (MgSO4), and
evaporated in vacuo. The residue was chromatographed on silica
gel using hexane–CH2Cl2 (1:2) as eluent to give 3A and 4A. The
crystalline product was recrystallized from hexane.
IR: n = 3272 (NH), 2214 (CC), 1640 cm–1 (C=0).
1H NMR (60 MHz): d = 0.97, 1.2–1.8 and 3.45 (3H, t, J = 6 Hz, 4H,
m and 2H, br t, J = 6 Hz, N-Bu), 2.06 (3H, s, Me), 7.2–7.5 and 7.9–
8.1 (3H, m and 1H, m, PhH), 7.7 (1H, br, NH).
Anal. Calcd. for C14H17ON: C, 78.10; H, 7.96; N, 6.51. Found: C,
77.92; H, 7.87; N, 6.62.
1Bb (R = Bu): colorless prisms, mp 57–60 °C; yield: 2.05 g
(80%).
MS: m/z = 257 (M+).
IR: n = 3284 (NH), 2232 (CC), 1644 cm–1 (C=O).
1H NMR (60 MHz): d = 1.0, 1.1–1.9, 2.47 and 3.46 (6H, m, 8H, m,
2H, t, J = 6 Hz and 2H, br t, J = 6 Hz, N-Bu and Bu), 7.3–7.5 and
8.0–8.1 (3H, m and 1H, m, PhH), 7.6 (1H, br NH).
3Aa (R = Me): colorless prisms, mp 69–73 °C (lit.16 mp 71 °C); 130
mg (81%).
3Ab (R = Bu): colorless prisms, mp 45–46 °C (lit.16 mp 44 °C); 147
mg (73%).
Anal. Calcd. for C17H23ON: C, 79.33; H, 9.01; N, 5.44. Found: C,
78.66; H, 9.16; N, 5.49.
3Ac (R = t-Bu): colorless prisms, mp 62–65 °C (lit.16 mp 61 °C); 97
mg (48%).
1Bc (R = t-Bu): colorless oil; yield: 2.30 g (90%).
MS: m/z = 257 (M+).
4Ac (R = t-Bu): colorless prisms, mp 90–91 °C; yield: 77 mg (38%).
MS: m/z = 202 (M+).
IR: n = 1788 cm–1 (C=O).
1H NMR (90 MHz): d = 1.32 (9H, s, t-Bu), 5.60 (1H, s, 3’-H), 7.48–
7.68 and 7.88 (3H, m and 1H, d, J = 7.7 Hz, PhH).
IR: n = 3324 (NH), 2236 (CC), 1654 cm–1 (C=O).
1H NMR (60 MHz): d = 0.95, 1.2–1.7 and 3.44 (3H, t, J = 6 Hz, 4H,
m and 2H, br t, J = 6 Hz, N-Bu), 1.34 (9H, s, t-Bu), 7.2–7.5 and 7.9–
8.1 (3H, m and 1H m, PhH), 7.9 (1H, br, NH).
HRMS m/z: M+ Calcd for C17H23ON: 257.1780. Found 257.1774.
Anal Calcd for C13H14O2: C, 77.20; H, 6.98. Found: C,76.64; H,
7.05.
1Bd (R = Ph): colorless prisms, mp 123–125 °C; yield: 1.83 g
(66%).
MS: m/z = 277 (M+).
IR: n = 3276 (NH), 2224 (CC), 1642 cm–1 (C=O).
3Ad (R = Ph): yellow prisms, mp 87–88 °C (lit. 16 mp 87–88 °C);
124 mg (56%).
1H NMR (60 MHz): d = 0.84, 1.2–1.8 and 3.50 (3H, t, J = 6 Hz, 4H,
m and 2H, br t, J = 6 Hz, N-Bu), 7.1–7.7 and 7.9–8.1 (9H, m and 1H
m, PhH and NH).
4Ad (R = Ph): colorless prisms, mp 86–88 °C; yield: 51 mg (23%).
MS: m/z = 222 (M+).
IR: n = 1766 cm–1 (C=O).
1H NMR (90 MHz): d = 6.46 (1H, s, 3’-H), 7.70–8.47 (9H, m, PhH).
HRMS m/z: M+ Calcd for C15H10O2: 222.0681. Found: 222.0685.
Anal. Calcd. for C19H19ON: C, 82.28; H, 6.90; N, 5.05. Found: C,
82.10; H, 7.15; N, 5.12.
1Be (R = TMS): yellow oil; yield: 0.74 g (27%).
MS: m/z = 273 (M+).
IR: n = 3120 (NH), 2160 (CC), 1664 cm–1 (C=O).
3Ae (R = TMS): colorless oil; yield: 68 mg (31%).
MS: m/z = 218 (M+).
Synthesis 1999, No. 7, 1145–1148 ISSN 0039-7881 © Thieme Stuttgart · New York

1148
H. Sashida, A. Kawamukai
PAPER
IR: n = 1726 cm–1 (C=O).
1H NMR (90 MHz): d = 0.28 (9H, s, TMS), 6.70 (1H, s, 4-H), 7.35–
7.89 and 8.23–8.43 (3H, m and 1H, m, PhH).
References
(1) (a) Lambert, C.; Uchimoto, K.; Nozaki, H., Tetrahedron Lett.
1984, 25, 5323 and cited therein.
HRMS m/z: M+ Calcd for C12H14O2Si: 218.0763. Found: 218.0761.
(b) Arcadi, A.; Burini, A.; Cacchi, S.; Delmastro, M.;
Marinelli, F.; Pietroni, B. R., J. Org. Chem. 1992, 57, 976.
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K.; Nozaki, H., Tetrahedron 1985, 41, 3655.
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Commun. 1994, 493.
(4) (a) Uchimoto, K.; Miwa, H.; Nozaki, H., Tetrahedron Lett.
1981, 22, 4277.
4Ae (R = TMS): yellow oil; yield: 89 mg (41%).
MS: m/z = 218 (M+).
IR: n = 1788 cm–1 (C=O).
1H NMR (90 MHz): d = 0.28 (9H, s, TMS), 5.66 (1H, s, 3’-H), 7.50–
8.01 (4H, m, PhH).
HRMS m/z: M+ Calcd for C12H14O2Si: 218.0763. Found: 218.0765.
(b) Iritani, K.; Matsubara, S.; Uchimoto, K., Tetrahedron Lett.
1988, 29, 1799.
(5) Tokuda, M.; Fujita, H.; Suginome, H., Tetrahedron Lett.
1990, 31, 5353.
Cyclization N-Butyl-o-ethynylbenzamide 1B: Fomation of Iso-
quinolin-1-one 3B; Typical Procedure
To a mixture of 1B (1mmol) and Et3N (0.5 mL) in anhyd THF (20
mL) was added PdPhCH2Cl(Ph3P)2 (25 mg, 0.03 mmol). The mix-
ture was refluxed with stirring until disappearance of the starting
material (about 12–20 h). Water was added to the mixture, and the
resulting aqueous mixture was extracted with CH2Cl2 (3 x 50 mL).
The combined organic extract was washed with brine (2 x 100 mL)
dried (MgSO4), and evaporated in vacuo. The residue was chro-
matographed on silica gel using CH2Cl2–acetone (30: 1) as eluent to
give 3B.
(6) (a) Sakamoto, T.; Kondo, Y.; Iwashita, S.; Nagano, T.;
Yamanaka, H., Chem. Pharm. Bull. 1988, 36, 1305.
(b) Arcadi, A,; Cacchi, S.; Marinelli, F., Tetrahedron Lett.
1992, 33, 3915.
(7) Sakamoto, T.; An-naka, M.; Kondo, Y.; Yamanaka, H., Chem.
Pharm. Bull. 1986, 34, 2754.
(8) Ohta, S.; Kamata, Y.; Inagaki, T.; Masuda, Y.; Yamamoto, S.;
Yamashita, M.; Kawasaki, I., Chem. Pharm. Bull. 1993, 416,
1181.
N-Butyl-3-methylisoquinolin-1-one 3Ba (R = Me)
Yellow oil, yield: 161 mg (75%).
(9) Minami, T.; Nishimoto, A.; Nakamura, Y.; Hanaoka, M.,
Chem. Pharm. Bull. 1994, 42, 1700.
(10) (a) Letsinger, R. L.; Oftendahl, E. N.; Nazy, J. R. J. Am. Chem.
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1966, 31, 2163.
MS: m/z = 215 (M+).
IR: n = 1656 cm–1 (C=O).
1H NMR (90 MHz): d = 0.97, 1.17–1.91 and 3.47 (3H, t, J = 6.4 Hz,
4H, m and 2H, t, J = 6.5 Hz, N-Bu), 2.12 (3H, s, Me),5.86 (1H, s, 4-
H), 7.01–7.55 and 8.18 (3H, m and 1H, d, J = 7.0 Hz, PhH).
(12) (a) Kundu, N. G.; Pal, M., J. Chem. Soc., Chem. Commun.
1993, 86.
HRMS m/z: M+ Calcd for C14H17ON: 215.1310. Found 215.1310.
N-Butyl-3-butylisoquinolin-1-one 3Bb (R = Bu)
Yellow oil; yield: 198 mg (77%).
(b) Kundu, N. G.; Pal, M.; Nandi, B., J. Chem. Soc., Perkin
Trans. 1 1998, 561.
MS: m/z = 257 (M+).
IR: n = 1654 cm–1 (C=O).
1H NMR (90 MHz): d = 0.72–1.93, 2.36 and 3.49 (14 H, m, 2H, t, J
= 6.0 Hz and 2H, t, J = 7.0 Hz, Bu and N-Bu), 5.83 (1H, s, 4-H),
6.97–7.54 and 8.17 (3H, m and 1H, d, J = 7.4 Hz, PhH).
(13) (a) Sashida, H.; Sadamori, K.; Tsuchiya, T. Synth. Commun.
1998, 28, 713.
(b) Sashida, H; Yasuike, S. J. Heterocycl. Chem. 1998, 35,
725.
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165.
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Chem. Commun. 1991, 802.
HRMS m/z: M+ Calcd for C17H23ON: 257.1780. Found 257.1779.
N-Butyl-3-phenylisoquinolin-1-one 3Bd (R = Ph)
Yellow oil; yield: 177 mg (64%).
(b) Sashida, H.; Ito, K.; Tsuchiya, T. J. Chem. Chem., Chem.
Commun. 1993, 1493.
MS: m/z = 277 (M+).
IR: n = 1642 cm–1 (C=O).
1H NMR (90 MHz): d = 0.98, 1.33–1.90 and 3.64 (3H, t, J = 6.6 Hz,
4H, m and 2H, t, J = 6.6 Hz, N-Bu), 6.56 (1H, s, 4-H), 7.27–7.47,
7.70–7.89 and 8.21 (5H, m, 3H, m and 1H, dd, J = 6.2, 2.2 Hz, PhH).
(c) Sashida, H. Synthesis 1998, 745.
(d) Sashida, H.; Kuroda, A.; Tsuchiya, T. Chem. Commun.
1998, 767.
(e) Sashida, H.; Ohyanagi, K. J. Chem. Chem., Perkin Trans.
1. 1998, 2123.
(f) Sashida, H.; Kuroda, A. Synthesis 1999, 921.
(16) Larock, R. C.; Varaprath, S.; Lau, H. H.; Fellows, C. A.,
J. Am. Chem. Soc. 1984, 106, 5274.
HRMS m/z: M+ Calcd for C19H19ON: 277.1467. Found 277.1461.
Article Identifier:
1437-210X,E;1999,0,07,1145,1148,ftx,en;F11699SS.pdf
Synthesis 1999, No. 7, 1145–1148 ISSN 0039-7881 © Thieme Stuttgart · New York